Compound 1-A1-antiP1

(14S,16R,17R,E)-14-hydroxy-4,14,16-trimethyl-17-(11-methyldodecyl)-8-methylene-1-oxa-4,9,12-triazacycloheptadec-6-ene-2,5,10,13,15-pentaone

From: Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products

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Synonyms:
  • (14S,16R,17R,E)-BE-43547A1

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

The starting alcohol 9 P1 (5.0 mg, 8.6 µmol, 1 equiv.) was dissolved in anhydrous THF (1.2 mL) in a dry flask under argon at rt. Et3N (15 µL, 108 µmol, 12.5 equiv.) was added followed by Ms2O (9 mg, 52 µmol, 6.0 equiv.). After 70 min TLC (95:5 EtOAc/MeOH, UV and CAM, see below) showed full conversion of the starting alcohol 9 P1. The reaction mixture was quenched with H2O and extracted four times with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was dissolved in DMSO-d6 for NMR analysis of the crude mixture. DBU (15 µL, 110 µmol, 12.8 equiv.) was added to the NMR tube, and the tube was shaken. H-NMR after 15 min showed full conversion of the mesylate. The product 1-A1-anti P1 (1.6 mg, 3 µmol, 33%) was obtained after HPLC purification and freeze-drying. The reaction was injected directly from the DMSO-d6 mixture. HPLC; H2O(A)/MeCN(B), 7 mL/min, 1x25 cm, C18, 5 µ 100 Å, 250 mm × 10 mm, Phenomenex, Luna, 254 nm, 280 nm. Gradient; 20%B to 80% (15 min), hold (6 min), to 100% B (1 min), hold (4 min). See section 2 in supporting information for a detailed discussion of formation, stability and purification of BE-43547A1 and diastereomers hereof. Rf 0.42 (EtOAc/MeOH 95:5, UV and CAM). 1H NMR (950 MHz, DMSO-d6) δ 8.77 (t, J = 6.5 Hz, 1H), 8.61 (brs, 1H), 6.96 (d, J = 15.2 Hz, 1H), 6.33 (d, J = 15.2 Hz, 1H), 5.59 (s, 1H), 5.39 (s, 1H), 4.98 (td, J = 9.5, 2.5 Hz, 1H), 4.31 (d, J = 18.0 Hz, 1H), 4.15 (d, J = 18.0 Hz, 1H), 3.95 (dd, J = 16.2, 6.4 Hz, 1H), 3.65 (dd, J = 16.2, 4.4 Hz, 1H), 3.40 (dq, J = 14.2, 7.1 Hz, 1H), 2.88 (s, 3H), 1.68 – 1.57 (m, 2H), 1.49 (dh, J = 13.2, 6.7 Hz, 1H), 1.46 (s, 3H), 1.30 – 1.15 (m, 16H), 1.13 (q, J = 7.0 Hz, 2H), 1.04 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 6.6 Hz, 6H). 13C NMR (239 MHz, DMSO) δ 209.8, 172.3, 168.1, 167.8, 166.0, 138.6, 137.9, 117.8, 114.8, 80.1, 74.7, 50.8, 43.3, 43.2, 38.5, 34.7, 30.8, 29.3, 29.0, 29.0, 28.9, 28.8, 27.4, 26.8, 24.1, 22.5, 21.7, 15.3. HRMS Calc.: C30H50N3O7+ 564.3643; found: 564.3653.

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